Vaccinate with Frodo

30. November 2010

It takes months to develop a vaccine against viruses in the computer, to breed it in chicken eggs to supply a safe vaccination. Faster and just as good is the stimulation of the immune system without protein in a syringe: With naked DNA-rings.

Steeled against the flue. Not by the annual vaccination but with only one vaccination in seventy years. It wasn’t a revolutionary new vaccine, Chih-Jen Wei and his colleagues at the American National Institute of Health published in “Science“ end of August. It wasn’t a new adjuvant either, just a novel combination of immunization and refresher with different vaccines. The most important about it: For the first stimulation of the immune system, the scientists did not use an isolated antigen or a synthetic peptide, but DNA from a stable, only little mutated region of the viral haematugglin-gene. The “boost” with a regular flue vaccination of one of the past years gave the ferrets, mice and monkeys a body’s defense against viruses dated back to 1934 just like against those of 2007.

Plasmid against adeno-virus

Time and again, the name “DNA-vaccine” is mentioned in relation with novel promising vaccinations. Actually, ten years ago the little nucleic acid elements, built into a ring-shaped plasmid molecule, were considered an obsolescent model. Researchers were hoping for the great breakthrough with two newly developed vaccines against HIV. An adeno-virus with a small piece HIV-DNA made the cell producing retroviral protein, thus leading to a measurable immune response. But the naked plasmid-DNA was disappointing. Its immune response was barely measurable.But several years later it paid off that the plasmid-developers had not thrown the towel: 2007 about 3000 participants in the “STEP-study” tested AdHu5, the vaccine with the viral vector. The result: Not any better than a placebo. The future again seems to belong to the “DNA-Drugs“. “Once they are matured, DNA-based vaccines and therapies can become a success story – for diseases we don’t have any effective treatment yet”, writes David Weiner, Professor for pathology and medicine at the University of Pennsylvania in his article for the “Scientific American”.

Not cooled long shelf life

In initial clinical studies, the unpacked DNA meanwhile brings an effective T-cell response against tumors induced by papilloma- or hepatitis-C viruses. Newly developed vaccinations against the bird flue rely on a common sequence of annual winter group and the known H5N1-strains. In May 2009, Vical, a company based in California/USA, developed an experimental swine flue vaccination based on DNA within two weeks. By now another vaccination against the AIDS-Virus has reached phase II of clinical studies where the plasmid-DNA has taken over the initial stimulation, the refresher is an adeno-virus with the according DNA-code piece. In comparison with conventional sera in the syringe, the new technology scores: The vaccine is stable in room temperature and thus “survives” even long-distance transportation without any larger efforts. And since plasmid is not foreign to the body, the immune system does not reject it. Contrary, in ideal cases the produced protein reacts strongly with the immune system – depending on what’s needed – mainly with B-cells and their antibodies or with T-cells.

With tattoo and current pulses to immunity

Out of the off, pure DNA as a vaccine molecule is in the game again of finding new ways in infection prevention, also by new strategies to transport the molecules into the cell’s interior. Like a canon, a “Gene Gun“ fires metal particles with the DNA-plasmids under the skin by gas pressure. Other technologies use nanoparticle, liposomes or “tattooing”, where a template transports the DNA via a lot of needles into the body all at once. The researchers are very optimistic that electroperation can strongly increase the efficiency of the expression. After all, experts say, that the cell increases antigen production by 10 to 1000 times if short current pulses open the cell membrane after infection and let the DNA rings go inside. Over the last years, many studies have shown that DNA plasmids are safe for the human being. If the right codon selection was made, there is no risk of recombination with the genotype. Also the risk of side effect – like with attenuated life vaccines – is significantly lower. Contrary, the DNA molecule per se already stimulates the production of type-I-interferons, important team mates in an immune response. Also unmethylated sequence motives – CpG-motive – promote recognition of TLR-9, one of the main actors of the innate immune system. And the adjuvant function as well can be built directly into the DNA by means of additional suitable sequences in the plasmid.

Help with asthma and transplanted organs

Until now hardly any DNA therapeutics and –vaccines are available on the market, at least not for humans. But in veterinarian areas DNA therapeutics have proved to be fit for example to prevent pregnant sows from miscarriage. And clinical studies with early childhood heart problem patients or x-chromosomal immune deficiency (SCID) in phase I and phase II have not been disappointing so far.

Pneumologists build on DNA as well. By using a short DNA piece of a TBC genome, the Swiss company Cytos developed an immune stimulant significantly decreasing allergic reactions of people suffering from asthma and thus the addiction to corticosteroids. DNA codes for histocompability molecules and T-cell receptors also direct against overreaction of the immune system. With this deliberately permanent tolerance induction, surgeons doing transplantations don’t have to be so picky with the selection of suitable organs any more.

Problems and obstacles?

Prokaryotic DNA pieces always hold a certain risk to mingle with benign commensals of the body and thus giving birth to new microbes with undesirable abilities. Antibiotic resistant genes required so far for the construction of the wanted plasmids, are supposed to vanish as soon as possible.

Home-made genotype from the lab as a protection against infections, cancer or autoimmune reactions – that sounds like a dangerous far away future vision. Last but not least the hot discussions about side effects and risks of those quickly developed vaccinations against swine flue show: Those days of breeding viruses in chicken eggs are coming to an end once there are safe alternatives.